Epigenetic modification in hypertrophied nuclei of the cardiomyocytes and its pathophysiological significance

• Project/Area Number: 16K09509
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Asahi University
• Principal Investigator: Genzou Takemura 朝日大学, 歯学部, 教授 (40283311)
• Co-Investigator(Kenkyū-buntansha): 金森 寛充 岐阜大学, 医学部附属病院, 講師 (20456502) ; 岡田 英志 岐阜大学, 医学部附属病院, 講師 (30402176)
• Research Collaborator: MATSUO Hitoshi ; MIYAZAKI Nagisa
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: エピジェネティクス / クロマチン・リモデリング / DNAメチル化 / 心不全 / 拡張型心筋症 / 心肥大 / 心筋細胞 / 肥大核 / ＤＮＡメチル化 / 超微形態 / 核肥大

Outline of Final Research Achievements

Methylated DNA was immunohistochemically detected in human endomyocardial biopsies. DNA methylation was greater in failing heart due to dilated cardiomyopathy (DCM, n=75) than in nonfailing hearts (n=20), of which increase was noted only in cardiomyocytes but not in other cell types. Methylated DNA predominantly localized on nuclear heterochromatin. DNA methylation was significantly correlated with hemodynamic parameters.
We treated 10-week-old delta-sarcoglycan deficient mice, an animal model of DCM, with 5-azacytidine, an inhibitor of DNA methylation at a dose of 1 mg/kg/day. Six weeks later, the survival rate was 100% in the treated mice while it was 69% in the vehicle-treated mice. We are now promoting the animal experiment by incorporating more mice and analyzing the cardiac tissue of the sacrificed mice pathologically and biochemically.

Academic Significance and Societal Importance of the Research Achievements

心筋細胞の肥大した核は従来その機能的意味が不明であったが、エピジェネティク変化ならびに病態との関連を明らかにすることでその意味の重要性を明らかにすることができる。
心不全動物モデルを用いて、エピジェネティック介入（ＤＮＡメチル化阻害薬）により心筋症の病態に変化が見られれば現実的かつ新しい心不全治療法のヒントがえられる可能性がある。

Research Products

• [Journal Article] Anti-apoptosis in nonmyocytes and pro-autophagy in cardiomyocytes: two strategies against postinfarction heart failure through regulation of cell death/degeneration (2018)
  • Author(s): Takemura Genzou、Kanamori Hiromitsu、Okada Hideshi、Miyazaki Nagisa、Watanabe Takatomo、Tsujimoto Akiko、Goto Kazuko、Maruyama Rumi、Fujiwara Takako、Fujiwara Hisayoshi
  • Journal Title: Heart Failure Reviews Volume: 23 Issue: 5 Pages: 759-772
  • DOI: 10.1007/s10741-018-9708-x
  • Peer Reviewed
• [Journal Article] Ultrastructural aspects of vacuolar degeneration of cardiomyocytes in human endomyocardial biopsies. (2017)
  • Author(s): Takemura G, Kanamori H, Okada H, Tsujimoto A, Miyazaki N, Takada C, Hotta Y, Takatsu Y, Fujiwara H.
  • Journal Title: Cardiovasc Pathol. Volume: 30 Pages: 64-71
  • DOI: 10.1016/j.carpath.2017.06.012
  • Peer Reviewed
• [Journal Article] Long-term pathological follow-up of myocardium in a carrier of Duchenne muscular dystrophy with dilated cardiomyopathy. (2017)
  • Author(s): Kondo T, Okumura T, Takefuji M, Hiraiwa H, Sugiura Y, Watanabe N, Aoki S, Ichii T, Kitagawa K, Kano N, Fukaya K, Furusawa K, Sawamura A, Morimoto R, Bano YK, Takemura G, Murohara T.
  • Journal Title: Circ Heart Fail. Volume: 10
  • NAID: 120006305563
  • Peer Reviewed
• [Journal Article] Liver fibrogenesis marker, 7S domain of collagen type IV in patients with acutely decompensated heart failure: Correlates, prognostic value and time course. (2017)
  • Author(s): Nagao K, Hayashi F, Inada T, Yukawa H, Morimoto T, Tanaka M, Shimamura K, Makita T, Tamura A, Takemura T, Kimura T, Sato Y, Ito H.
  • Journal Title: Int J Cardiol. Volume: 236 Pages: 483-487
  • DOI: 10.1016/j.ijcard.2017.01.089
  • Peer Reviewed
• [Journal Article] Mitochondrial cardiomyopathy diagnosed with histological and genetic analyses. (2017)
  • Author(s): Kuno T, Imaeda S, Asakawa Y, Nakamura H, Takemura G, Asahara D, Numasawa Y.
  • Journal Title: Case Rep Cardiol. Volume: 2017 Pages: 9473917-9473917
  • DOI: 10.1155/2017/9473917
  • Peer Reviewed / Open Access
• [Journal Article] Three dimensional ultrastructure of capillary endothelial glycocalyx under normal and septic conditions. (2017)
  • Author(s): Okada H, Takemura G, Suzuki K, Oda K, Takada C, Hotta Y, Miyazaki N, Tsujimoto A, Muraki I, Ando Y, Zaikokuji R, Matsumoto A, Kitagaki H, Tamaoki Y, Usui T, Doi T, Yoshida T, Yoshida S, Ushikoshi H, Toyoda I, Ogura S.
  • Journal Title: Critical Care. Volume: 26 Issue: 1 Pages: 261-261
  • DOI: 10.1186/s13054-017-1841-8
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial deformity confined to a single cardiomyocyte in human endomyocardial biopsy specimens: Report of 4 cases. (2017)
  • Author(s): Takemura G, Kanmori H, Okada H, Tsujimoto A, Miyazaki N, Miyata S, Ohta H, Kawase Y, Ono M, Mochizuki M, Kobayashi S, Onoue K, Nakano T, Sakaguchi Y, Matsuo H, Yano M, Saito Y.
  • Journal Title: J Cardiol Cases. Volume: 16 Pages: 178-182
  • Peer Reviewed
• [Journal Article] The effects of dipeptidyl peptidase-4 on cardiac fibrosis in pressure overload-induced heart failure. (2017)
  • Author(s): Hirose M, Takano H, Hasegawa H, Tadokoro H, Hashimoto N, Takemura G, Kobayashi Y.
  • Journal Title: J Pharmacol Sci. Volume: 135 Issue: 4 Pages: 164-173
  • DOI: 10.1016/j.jphs.2017.11.006
  • Peer Reviewed / Open Access
• [Journal Article] Non-invasive tissue characterization of lung tumors using integrated backscatter intravascular ultrasound: An ex vivo comparative study with pathological diagnosis. (2016)
  • Author(s): Ito F, Kawasaki M, Ohno Y, Toyoshi S, Morishita M, Kaito D, Yanase K, Funaguchi N, Asano M, Endo J, Mori H, Kobayashi K, Nishigaki K, Miyazaki T, Takemura G, Minatoguchi S.
  • Journal Title: Chest. Volume: 149 Issue: 5 Pages: 1276-1284
  • DOI: 10.1378/chest.14-3042
  • Peer Reviewed
• [Journal Article] An oxidative stress biomarker, urinary 8-hydroxy-2'-deoxyguanosine, predicts cardiovascular-related death after steroid therapy for patients with active cardiac sarcoidosis. (2016)
  • Author(s): Myoren T, Kobayashi S, Oda S, Nanno T, Ishiguchi H, Murakami W, Okuda S, Okada M, Takemura G, Suga K, Matsuzaki M, Yano M.
  • Journal Title: Int J Cardiol Volume: 17 Pages: 206-213
  • DOI: 10.1016/j.ijcard.2016.03.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Electron microscopic findings are an important aid for diagnosing mitochondrial cardiomyopathy with mitochondrial DNA mutation 3243A>G. (2016)
  • Author(s): Takemura G, Onoue K, Kashimura T, Kanamori H, Okada H, Tsujimoto A, Miyazaki N, Nakano T, Sakaguchi Y, Saito Y.
  • Journal Title: Circulation: Heart Failure. Volume: 9 Issue: 7
  • DOI: 10.1161/circheartfailure.116.003283
  • Peer Reviewed
• [Journal Article] Deletion of CD28 Co-stimulatory Signals Exacerbates Left Ventricular Remodeling and Increases Cardiac Rupture After Myocardial Infarction (2016)
  • Author(s): Kubota A, Hasegawa H, Tadokoro H, Hirose M, Kobara Y, Yamada-Inagawa T, Takemura G, Kobayashi Y, Takano H.
  • Journal Title: Circulation Journal Volume: 80 Issue: 9 Pages: 1971-1979
  • DOI: 10.1253/circj.CJ-16-0327
  • NAID: 130005406870
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Presentation] In Situ Nuclear DNA Methylation in Human Failing Hearts with Dilated Cardiomyopathy. (2019)
  • Author(s): Watanabe T, Okada H, Kanamori H, Miyazaki N, Tsujimoto A, Takada C, Suzuki K, Nawa T, Tanaka T, Kawasaki M, Ogura S, Hotta Y, Fujiwara T, Fujiwara H, Takemura G.
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] In situ nuclear DNA methylation in human failing hearts with dilated cardiomyopathy. (2018)
  • Author(s): Watanabe T, Okada H, Kanamori H, Miyazaki N, Tsujimoto A, Nawa T, Tanaka T, Kawasaki M, Fujiwara T, Fujiwara H, Takemura G.
  • Organizer: 2018 Congress of European Society of Cardiology
  • Int'l Joint Research
• [Presentation] 特別講演「循環器疾患におけるオートファジー ―基礎と臨床―」 (2017)
  • Author(s): 竹村元三
  • Organizer: 第２回循環器疾患地域連携フォーラム
  • Place of Presentation: 尼崎
  • Year and Date: 2017-03-23
• [Presentation] 特別講演「心筋疾患の病理診断」 (2017)
  • Author(s): 竹村元三
  • Organizer: 第14回GINCS (Gifu Nuclear Cardiology Salon)
  • Place of Presentation: 岐阜
  • Year and Date: 2017-03-08
• [Presentation] 医療薬学・分子血管薬理学特論：心血管疾患の病態Ⅱ 「心疾患におけるアポトーシスの意義」 (2017)
  • Author(s): 竹村元三
  • Organizer: 千葉大学大学院薬学部講義
  • Place of Presentation: 千葉
  • Year and Date: 2017-01-26
• [Presentation] DPP-4 inhibition ameriolates the progression of heart failure after pressure overload through modulation of collagen type 3. (2017)
  • Author(s): Hirose M, Takano H, Hasegawa H, Hashimoto N, Tadokoro H, Takemura G, Kobayashi Y.
  • Organizer: 2017 Congress of European Society of Cardiology
  • Int'l Joint Research
• [Presentation] Thrombomodulin Attenuates Sepsis-induced Myocardial Dysfunction via Protection of Endothelial Glycocalyx Structure. (2017)
  • Author(s): Yamaji F, Okada H, Takemura G, Suzuki S, Takada C, Miyazaki N, Ogura S.
  • Organizer: 2017 Congress of American Heart Association
  • Int'l Joint Research
• [Presentation] Neutrophil Elastase Plays a Pivotal Role in Sepsis-induced Myocardial Dysfunction. (2017)
  • Author(s): Suzuki K, Okada H, Takemura G, Yamaji F, Takada C, Oda K, Hotta Y, Miyazaki N, Doi T, Yoshida T, Yoshida S, Ushikoshi H, Ogura S.
  • Organizer: 2017 Congress of American Heart Association
  • Int'l Joint Research
• [Presentation] Metformin Displays Cardioprotection in δ-sarcoglycan Deficiency Induced Cardiomyopathy Through Autophagic Activation via AMPK-mTOR Pathway. (2017)
  • Author(s): Kanamori H, Naruse G, Yoshida A, Minatoguchi S, Komaki H, Baba S, Yamada Y, Mikami A, Kawasaki M, Nishigaki K, Takemura G, Minatoguchi S.
  • Organizer: 2017 Congress of American Heart Association
  • Int'l Joint Research
• [Presentation] シンポジウム：リバースリモデリングはどこまで可能か？―分子機構を探るー 「アポトーシス・オートファジー制御による梗塞後リモデリングの改変」 (2016)
  • Author(s): 竹村元三
  • Organizer: 第33回国際心臓研究会日本部会(ISHR2016)
  • Place of Presentation: 東京
  • Year and Date: 2016-12-16
• [Presentation] シンポジウム：空胞病変の見方 「空胞病変の電子顕微鏡診断」 (2016)
  • Author(s): 竹村元三
  • Organizer: 第38回心筋生検研究会
  • Place of Presentation: 東京
  • Year and Date: 2016-11-26
• [Presentation] 「心筋生検の役割と特定心筋疾患について」 (2016)
  • Author(s): 竹村元三
  • Organizer: 日本循環器学会教育研修委員会E-ラーニング
  • Place of Presentation: 東京
  • Year and Date: 2016-09-24
• [Presentation] シンポジウム：心筋症の画像診断 「心筋症診療における組織診の有用性」 (2016)
  • Author(s): 尾上健児、中野知哉、坂口泰弘、竹村元三、瀬藤光利、斉藤能彦
  • Organizer: 第2回心筋症研究会
  • Place of Presentation: 松本
  • Year and Date: 2016-05-14
• [Presentation] シンポジウム：心筋炎/心筋症 「糖尿病性心筋症の基礎と臨床―オートファジーの関与―」 (2016)
  • Author(s): 金森寛充、竹村元三、川崎雅規、西垣和彦、湊口信也
  • Organizer: 第2回心筋症研究会
  • Place of Presentation: 松本
  • Year and Date: 2016-05-14
• [Book] 診断モダリティとしての心筋病理 (2017)
  • Author(s): 竹村元三、他
  • Total Pages: 214
  • Publisher: 南江堂
• [Book] 電子顕微鏡アトラス ラットの正常構造(1)肝臓 (2017)
  • Author(s): 佐藤茂、安達彰子、佐佐木喜広、戴威、竹村元三
  • Total Pages: 30
  • Publisher: 東京電子顕微鏡相談室